Heart failure is an illness in which the heart is unable to pump enough blood to meet the body’s metabolic requirements. Heart failure is a chronic progressive illness — many patients experience episodes of acute decompensation (worsening of their heart failure) which require hospitalization. Heart failure is a serious illness. There is a significant need for new, innovative treatments that can both halt the progression of the illness and reverse the negative effects, leading to improved outcomes for patients.
Our heart failure program is focused on the natriuretic peptide receptor system. This system has numerous cardiovascular functions. We are developing synthetic mimetics of natural neuropeptide hormones, including mimetics of atrial natriuretic peptide and other natriuretic peptides. Many heart failure patients have insufficient active natriuretic peptides. This contributes to worsening heart failure.
Our Lead Heart Failure Product Candidate
Our lead heart failure product candidate is PL-3994. PL-3994 is a subcutaneously injected guanylate-cyclase type A (GC-A) receptor agonist. It is in development for patients with heart failure (NYHA Class II-IV) to reduce the risk of cardiovascular death and hospitalization. PL-3994 is also being developed for heart failure patients with a loss-of-function corin mutation or other clinically meaningful natriuretic peptide system deficiencies, a patient population that is particularly resistant to the current standard of care. Corin is an enzyme that converts inactive natriuretic prohormone into active hormone.
Clinical studies have shown that PL-3994 is a potent GC-A agonist, with a half-life suitable for chronic subcutaneous self-administration, with pharmacokinetic and pharmacodynamic properties superior to other natriuretic peptides, including products approved in the U.S. and elsewhere.
The natriuretic peptide system (NPS) provides critical compensatory actions that oppose the pathophysiological changes caused by heart failure. The NPS is one of the body’s primary mechanisms for addressing the disease processes which underlie heart failure. The NPS is a well validated but under exploited target for the development of novel heart failure treatments.
Research conducted in academic laboratories and by Palatin demonstrate that the second generation of agonists directed at GC-A receptors, such as PL-3994, can have profound effects on reducing cardiac hypertrophy and fibrosis, downregulating the renin-angiotensin-aldosterone system (RAAS) and restoring cardiac function without causing hypotension. The ability to address disease processes at non-hypotensive doses is key to the commercial potential of this approach.
What is the Clinical Development Status of PL-3994?
Palatin has conducted two placebo controlled single ascending dose Phase I studies. In the first study, PL-3994 was administered as a single subcutaneous dose to healthy subjects. The second study administered a single subcutaneous dose of PL-3994 to subjects with controlled hypertension. In both studies endpoints included: safety, blood pressure, heart rate, diuresis, natriuresis and cyclic guanosine monophosphate (cGMP) plasma levels. Treatment was well tolerated, with no acute safety concerns and a dose response for prolonged pharmacological effects. The duration of action (8-12 hours) and pharmacology support chronic use.
What are the Next Steps in Development of PL-3994?
We plan to conduct a multiple ascending dose escalation study in heart failure subjects this year. The study population will include patients with stable NYHA II-III heart failure and a subset of patients with a loss-of-function corin gene mutation. We are also developing a protocol for a subsequent Phase IIb proof-of-principle clinical trial in patients with heart failure, with treatment for a three to six month period, and evaluation of cardiac function, effects on remodeling, symptom improvement and hospitalization admission rates.